A particular example is the Polymerase Chain Reaction method (often referred to as PCR) for replicating DNA samples. Such samples require rapid and accurate thermal cycling, and are typically placed in a multi-well block and cycled between several selected temperatures in a pre-set repeated cycle. It is important that the temperature of the whole of the sheet or more particularly the temperature in each well be as uniform as possible.
The samples are normally liquid solutions, typically between 1 micro-1 and 200 micro-1 in volume, contained within individual sample tubes or arrays of sample tubes that may be part of a monolithic plate. It is desirable to minimise temperature differentials within the volume of an individual sample during thermal processing. The temperature differentials that may be measured within a liquid sample increase with increasing rate of change of temperature and may limit the maximum rate of change of temperature that may be practically employed.
Previous methods of heating such specimen carriers have involved the use of attached heating devices such as wire, strip and film elements and Peltier effect thermoelectric devices, or the use of indirect methods where separately heated fluids are directed into or around the carrier
The previous methods of heating suffer from the disadvantage that heat is generated in a heater that is separate from the specimen carrier that is required to be heated.
The thermal energy must then be transferred from the heater to the carrier sheet which, in the case of an attached heater element, occurs through an insulating barrier and in the case of a fluid transfer mechanism occurs by physically moving fluid from the heater to the sheet.
The separation of the heater from the block introduces a time delay or “lag” in the temperature control loop. That is to say that the application of power to the heating elements does not produce an instantaneous or near instantaneous increase in the temperature of the block. The presence of a thermal gap or barrier between the heater and the block requires the heater to be hotter than the block if heat energy is to be transferred from the heater to the block. Therefore, there is a further difficulty that cessation of power application to the heater does not instantaneously stop the block from increasing in temperature.
The lag in the temperature control loop will increase as the rate of temperature change of the block is increased. This can lead to inaccuracies in temperature control and limit the practical rates of change of temperature that may be used.
Inaccuracies in terms of thermal uniformity and further lag may be produced when attached heating elements are used, as the elements are attached at particular locations on the block and the heat produced by the elements must be conducted from those particular locations to the bulk of the block. For heat transfer to occur from one part of the block to another, the first part of the block must be hotter than the other.
Another problem with attaching a thermal element, particularly a Peltier effect device, is that the interface between the block and the thermal device will be subject to mechanical stresses due to differences in the thermal expansion coefficients of the materials involved. Thermal cycling will lead to cyclic stresses that will tend to compromise the reliability of the thermal element and the integrity of the thermal interface.
Our PCT application GB97/00195 has disclosed a novel method where the specimen carrier is metallic and an alternating current is applied to the metallic specimen carrier in order to provide direct resistive heating. The Specification of the aforesaid PCT application discloses various features of heating the carrier and the whole of that disclosure is part of this Specification.
Our PCT application GB01/01284 discloses a method of heating a specimen carrier by applying an alternating current through the specimen carrier and relying upon resistive heating to provide direct heating of the carrier. An added benefit of this method of heating is that magnetically responsive stirrers placed in each specimen well are agitated by the applied current. The whole of the disclosure of that patent application is part of this Specification.
Direct resistive heating has no practical power limitations, and is the preferred means of heating in just about every respect, particularly when rapidly thermal cycling PCR samples. However, one disadvantage of direct resistive heating is that it precludes zonal heating of specimen carriers, which is required for certain applications. In zonal heating, different zones or regions of a carrier are heated to a different extent. Zonal heating is relatively easily implemented by the use of several heating elements attached to the carrier. Differential heating applied by the elements allows zonal heating of the carrier to be achieved. Needless to say, this method suffers all of the disadvantages of the prior art described in the foregoing. Hence there is a requirement for a zonal heating system for carriers which does not suffer the problems of indirect heating of the specimen carrier.